Elastase is one of the serine proteases, an important family of enzymes within the proteolytic enzyme group whose members are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, the immune reaction to foreign cells and organisms and the fertilization of the ovum by the spermatozoon. The proteolytic or protein cutting enzymes are proteins whose function is to alter or decompose other proteins by splitting them into fragments. Elastase acts on bonds in the middle of the protein chain which are adjacent to aliphatic amino acids.
Proteases may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto. Naturally occurring protease inhibitors form part of the control or defense mechanisms that are crucial to the well-being of the organism, as the protease enzymes would destroy any protein within reach, including themselves. The naturally occurring enzyme inhibitors have evolved a configuration in the binding region that closely resembles the bound substrate, which is part of the reason they bind to the enzyme so tightly (see Stroud, "A Family of Protein-Cutting Proteins" Sci. Am. July 1974, p. 74-88).
.alpha..sub.1 -Antitrypsin, a glycoprotein in human serum, has a wide inhibitory spectrum covering trypsin, chymotrypsin, plasmin, kallikrein, elastase, thrombin and a protease from Aspergillus oryzae. The marked reduction in serum .alpha..sub.1 -antitrypsin has been associated with pulmonary emphysema (see Erickson, S. "Pulmonary emphysema and alpha.sub.1 -antitrypsin deficiency" Acta. Med. Scand. 1964, 175, 197). Subsequent studies have confirmed and extended this observation (see Morse et al. "A Community Study of the Relation of Alpha.sub.1 -Antitrypsin Levels to Obstructive Lung Diseases" The New England Journal of Medicine, Vol. 292, No. 6, p. 278, Feb. 6, 1975).
Emphysema has been experimentally induced in laboratory animals by aerosolization into the tracheobronchial tree of the proteolytic enzyme, papain, and more recently by dog polymorphonuclear enriched leukocyte homogenates (see Mass et al. "Induction of Experimental Emphysema" American Review of Respiratory Disease, vol. 106, p. 384, 1972). The pathological changes are similar to and closely resemble human pulmonary emphysema. Also, intratracheally instilled elastase produces marked alterations in lung elastin with dilatation of alveolar ducts and alveoli (see Johanson et al. "Comparison of elastase, collagenase and papain on lung structure and function" Amer. Rev. Resp. Dis. 1971, 103, 908). Papain induced emphysema has been inhibited in the hamster by human .alpha..sub.1 -antitrypsin (HAAT). Since papain is one of the few proteinases not inhibited by HAAT, the HAAT inhibits the elastase-like enzymes released by polymorphonuclear leukocytes and alveolar macrophages which invade the hamsters' lungs following exposure (see Martorana et al. "Inhibition of Papain-Induced Emphysema in the Hamster by Human Alphal-antitrypsin," Can. J. Physiol. Pharmacol. Vol. 52, No. 3, p. 758-759, 1974 and Kaplan et al. "The induction of emphysema with elastase" Journal of Laboratory and Clinical Medicine, vol. 82, No. 3, 349-356, Sept. 1973). Elastase inhibitors may be used in control of elastase-like enzymes released by polymorphonuclear leukocytes and alveolar macrophages in emphysema.
In rheumatoid arthritis, antigen/antibody complexes have been demonstrated in the synovial fluid and as cytoplasmic inclusions in leukocytes which are chemotactically attracted to the sites of inflammation (see Oronsky et al. "Release of Cartilage Mucopolysaccharide Degrading Neutral Protease from Human Leukocytes", Journal of Experimental Medicine, vol. 138, p. 461-472, 1973). Polymorphonuclear leukocytes (PMN) enter acute inflammatory exudates to phagocytize the immune reactants or microorganisms. During phagocytosis, PMN enzymes are sometimes released extracellularly. When the extracellular release occurs to a degree sufficient to overwhelm the host inhibitors, tissue damage produced by the PMN substances may greatly diminish their beneficial effects. The major portion of neutral proteolylic activity in humans is usually attributed to elastin-like enzymes (see Janoff, "Alanine p-nitrophenyl esterase activity of human leukocyte granules", Biochemical Journal, 114; p. 157-159, 1969). Elastase inhibitors can be used to control PMN mediated tissue damage in acute inflammatory diseases of immunological origin, such as rheumatoid arthritis, caused by elastase.